tbuckley/cabot-search huggingface dataset:
The ROWAN study: Safety and efficacy of transarterial radioembolization with Y-90 glass microspheres and the STRIDE regimen in hepatocellular carcinoma.
Authors: Aiwu Ruth He, Beau Toskich
Journal: Journal of Clinical Oncology (2023)

TPS622 Background: In patients with early and intermediate hepatocellular carcinoma (HCC) who are ineligible for resection, thermal ablation, or liver transplant, transarterial radioembolization (TARE) with yttrium-90 glass microspheres has shown superior efficacy compared to transarterial chemoembolization; a subset of patients progress despite effective local therapy. Immunotherapy using the single tremelimumab regular interval durvalumab (STRIDE) regimen has demonstrated superior overall survival to sorafenib in advanced HCC. Recent work showed that TARE upregulates both the innate and adaptive immune systems. The possibility for TARE and STRIDE to have additive or synergistic effects when combined is of current scientific and clinical interest. The primary objective of the Phase II ROWAN Study is to assess the objective response rate and durability of local tumor control with TARE followed by STRIDE vs. TARE alone. Methods: ROWAN is a global, open-label, prospective, multicenter randomized controlled trial comparing treatment with TARE using glass microspheres followed by the STRIDE regimen (a single dose of 300 mg tremelimumab combined with 1500 mg monthly dose of durvalumab for 18 months) to TARE alone in HCC. ROWAN will include 150 patients across approximately 20 study sites in North America and Europe. Key inclusion criteria: HCC, diagnosed by radiographic imaging or histology; ineligible for or declined liver resection, thermal ablation, or transplantation; Child-Pugh A; ECOG 0; life expectancy ≥6 months; treatment naïve; unilobar tumor; measurable by mRECIST; tumor volume ≤25% of whole liver volume; and untreated future liver remnant volume ≥30% of whole liver volume. Key exclusion criteria: extrahepatic metastases; shunt fraction with a lung dose of &gt;30 Gy; macrovascular invasion; infiltrative disease not evaluable by mRECIST; history of any organ allograph; autoimmune or inflammatory disorder; current use of immunosuppressive medication; history of malignancy other than HCC within past 3 years; and active infection. Patients will be randomized in a 1:1 ratio to two study arms (TARE followed by STRIDE or TARE alone) using two stratification factors (TARE treatment goal [ablative vs. non-ablative] and alpha fetoprotein level [&gt;400 vs. ≤400 ng/mL]). Tumor and blood samples will be collected for correlative studies. Co-primary efficacy endpoints are objective response rate and duration of response (localized mRECIST). The primary safety endpoint is the number of adverse events (AEs) and serious AEs. Interim statistical analyses will be conducted after 25 patients have been randomized to each arm and completed the second imaging assessment 6 months post-randomization; final analysis will be after the last evaluable patient has completed the 18 months follow-up visit post-randomization or discontinued treatment. Clinical trial information: 05063565 .
Multinational Analysis of Estimated Health Care Costs Related to Extended-Interval Fixed Dosing of Checkpoint Inhibitors
Authors: Daniel A. Goldstein, Gary M. Ginsberg, Dorit Hofnung-Gabbay, Richard De Abreu Lourenco, Herbert H. Loong, Boon Cher Goh, Kelvin K. W. Chan, Massimo Di Maio, Francesco Perrone, Peter S. Hall, Alona Zer, Eli Rosenbaum
Journal: JAMA Network Open (2023)

New dosing options for immune checkpoint inhibitors have recently been approved by the US Food and Drug Administration (FDA), including fixed dosing with extended intervals. Although the dose intensity appears the same, there is expected to be some waste with extended-interval dosing, as some drug remains in the bloodstream once a decision to stop treatment is made. The economic impact of extended-interval fixed dosing is unknown compared with standard-interval fixed dosing.To analyze the potential health care costs of using extended-interval fixed dosing instead of standard-interval fixed dosing.This economic evaluation used a pharmacoeconomic model to simulate 2 cohorts of patients with platinum-resistant metastatic urothelial cancer receiving pembrolizumab as second-line therapy at different dosing intervals using 2020 pricing data. Data were analyzed from 2020 to 2022.The simulated patients received FDA-approved regimens of either 200 mg every 3 weeks or 400 mg every 6 weeks.The progression-free survival curve from the KEYNOTE-045 trial was used to estimate treatment duration. Drug, imaging, and administration costs were included in analyses. Sensitivity analyses were performed to assess how different imaging frequencies would affect the model results. The potential overall costs of using the 2 different dosing strategies were assessed. The base case was set in the US, while sensitivity analyses were set in several other countries.In the base case analysis, dosing every 6 weeks instead of every 3 weeks resulted in an estimated 8.9% increase in pembrolizumab costs for the health care payer. Accounting for a decrease in infusion costs would result in an estimated net additional cost of $7483 per patient in the US (7.9% cost increase). In the US, this would amount to an increase of approximately $28 million annually for health care payers. Similar percentages in cost estimate increases were found for health care payers around the world, such as in Israel, where the net additional cost would be $5491 per patient.This economic evaluation assessed and quantified the potential increased costs related to extended-interval fixed dosing of pembrolizumab. The model method could be applied to other diseases and other drugs for which there has been a movement toward extended-interval dosing. Results may differ in other diseases owing to differing disease courses and patient profiles.
Characterization of Mental Health in US Veterans Before, During, and 2 Years After the Onset of the COVID-19 Pandemic
Authors: Ian C. Fischer, Peter J. Na, Ilan Harpaz-Rotem, John H. Krystal, Robert H. Pietrzak
Journal: JAMA Network Open (2023)

This cohort study of US veterans reports changes in rates of anxiety and depressive disorders following the COVID-19 pandemic.
Exposure to US Cancer Drugs With Lack of Confirmed Benefit After US Food and Drug Administration Accelerated Approval
Authors: Ravi B. Parikh, Rebecca A. Hubbard, Erkuan Wang, Trevor J. Royce, Aaron B. Cohen, Amy S. Clark, Ronac Mamtani
Journal: JAMA Oncology (2023)

This cross-sectional study evaluates patient exposure to oncology drugs withdrawn from the US Food and Drug Administration (FDA) Accelerated Approval program.
Estimates and Projections of the Global Economic Cost of 29 Cancers in 204 Countries and Territories From 2020 to 2050
Authors: Simiao Chen, Zhong Cao, Klaus Prettner, Michael Kuhn, Juntao Yang, Lirui Jiao, Zhuoran Wang, Weimin Li, Pascal Geldsetzer, Till Bärnighausen, David E. Bloom, Chen Wang
Journal: JAMA Oncology (2023)

Cancers are a leading cause of mortality, accounting for nearly 10 million annual deaths worldwide, or 1 in 6 deaths. Cancers also negatively affect countries' economic growth. However, the global economic cost of cancers and its worldwide distribution have yet to be studied.To estimate and project the economic cost of 29 cancers in 204 countries and territories.A decision analytical model that incorporates economic feedback in assessing health outcomes associated with the labor force and investment. A macroeconomic model was used to account for (1) the association of cancer-related mortality and morbidity with labor supply; (2) age-sex-specific differences in education, experience, and labor market participation of those who are affected by cancers; and (3) the diversion of cancer treatment expenses from savings and investments. Data were collected on April 25, 2022.Economic cost of 29 cancers across countries and territories. Costs are presented in international dollars at constant 2017 prices.The estimated global economic cost of cancers from 2020 to 2050 is $25.2 trillion in international dollars (at constant 2017 prices), equivalent to an annual tax of 0.55% on global gross domestic product. The 5 cancers with the highest economic costs are tracheal, bronchus, and lung cancer (15.4%); colon and rectum cancer (10.9%); breast cancer (7.7%); liver cancer (6.5%); and leukemia (6.3%). China and the US face the largest economic costs of cancers in absolute terms, accounting for 24.1% and 20.8% of the total global burden, respectively. Although 75.1% of cancer deaths occur in low- and middle-income countries, their share of the economic cost of cancers is lower at 49.5%. The relative contribution of treatment costs to the total economic cost of cancers is greater in high-income countries than in low-income countries.In this decision analytical modeling study, the macroeconomic cost of cancers was found to be substantial and distributed heterogeneously across cancer types, countries, and world regions. The findings suggest that global efforts to curb the ongoing burden of cancers are warranted.
A Competition, Benchmark, Code, and Data for Using Artificial Intelligence to Detect Lesions in Digital Breast Tomosynthesis
Authors: Nicholas Konz, Mateusz Buda, Hanxue Gu, Ashirbani Saha, Jichen Yang, Jakub Chłędowski, Jungkyu Park, Jan Witowski, Krzysztof J. Geras, Yoel Shoshan, Flora Gilboa-Solomon, Daniel Khapun, Vadim Ratner, Ella Barkan, Michal Ozery-Flato, Robert Martí, Akinyinka Omigbodun, Chrysostomos Marasinou, Noor Nakhaei, William Hsu, Pranjal Sahu, Md Belayat Hossain, Juhun Lee, Carlos Santos, Artur Przelaskowski, Jayashree Kalpathy-Cramer, Benjamin Bearce, Kenny Cha, Keyvan Farahani, Nicholas Petrick, Lubomir Hadjiiski, Karen Drukker, Samuel G. Armato, Maciej A. Mazurowski
Journal: JAMA Network Open (2023)

Importance An accurate and robust artificial intelligence (AI) algorithm for detecting cancer in digital breast tomosynthesis (DBT) could significantly improve detection accuracy and reduce health care costs worldwide. Objectives To make training and evaluation data for the development of AI algorithms for DBT analysis available, to develop well-defined benchmarks, and to create publicly available code for existing methods. Design, Setting, and Participants This diagnostic study is based on a multi-institutional international grand challenge in which research teams developed algorithms to detect lesions in DBT. A data set of 22 032 reconstructed DBT volumes was made available to research teams. Phase 1, in which teams were provided 700 scans from the training set, 120 from the validation set, and 180 from the test set, took place from December 2020 to January 2021, and phase 2, in which teams were given the full data set, took place from May to July 2021. Main Outcomes and Measures The overall performance was evaluated by mean sensitivity for biopsied lesions using only DBT volumes with biopsied lesions; ties were broken by including all DBT volumes. Results A total of 8 teams participated in the challenge. The team with the highest mean sensitivity for biopsied lesions was the NYU B-Team, with 0.957 (95% CI, 0.924-0.984), and the second-place team, ZeDuS, had a mean sensitivity of 0.926 (95% CI, 0.881-0.964). When the results were aggregated, the mean sensitivity for all submitted algorithms was 0.879; for only those who participated in phase 2, it was 0.926. Conclusions and Relevance In this diagnostic study, an international competition produced algorithms with high sensitivity for using AI to detect lesions on DBT images. A standardized performance benchmark for the detection task using publicly available clinical imaging data was released, with detailed descriptions and analyses of submitted algorithms accompanied by a public release of their predictions and code for selected methods. These resources will serve as a foundation for future research on computer-assisted diagnosis methods for DBT, significantly lowering the barrier of entry for new researchers.
Glycolysis drives STING signaling to facilitate dendritic cell antitumor function
Authors: Zhilin Hu, Xiaoyan Yu, Rui Ding, Ben Liu, Chuanjia Gu, Xiu-Wu Pan, Qiaoqiao Han, Yuerong Zhang, Jie Wan, Xin-Gang Cui, Jiayuan Sun, Qiang Zou
Journal: Journal of Clinical Investigation (2023)

Activation of STING signaling in DCs promotes antitumor immunity. Aerobic glycolysis is a metabolic hallmark of activated DCs, but how the glycolytic pathway intersects with STING signaling in tumor-infiltrating DCs remains elusive. Here, we show that glycolysis drives STING signaling to facilitate DC-mediated antitumor immune responses. Tumor-infiltrating DCs exhibited elevated glycolysis, and blockade of glycolysis by DC-specific Ldha/Ldhb double deletion resulted in defective antitumor immunity. Mechanistically, glycolysis augmented ATP production to boost STING activation and STING-dependent DC antitumor functions. Moreover, DC-intrinsic STING activation accelerated HIF-1α-mediated glycolysis and established a positive feedback loop. Importantly, glycolysis facilitated STING-dependent DC activity in tissue samples from patients with non-small cell lung cancer. Our results provide mechanistic insight into how the crosstalk of glycolytic metabolism and STING signaling enhances DC antitumor activity and can be harnessed to improve cancer therapies.
Complementary lateral hypothalamic populations resist hunger pressure to balance nutritional and social needs
Authors: Anne Petzold, Hanna Elin van den Munkhof, Rebecca Figge-Schlensok, Tatiana Korotkova
Journal: Cell Metabolism (2023)

Animals continuously weigh hunger and thirst against competing needs, such as social contact and mating, according to state and opportunity. Yet neuronal mechanisms of sensing and ranking nutritional needs remain poorly understood. Here, combining calcium imaging in freely behaving mice, optogenetics, and chemogenetics, we show that two neuronal populations of the lateral hypothalamus (LH) guide increasingly hungry animals through behavioral choices between nutritional and social rewards. While increased food consumption was marked by increasing inhibition of a leptin receptor-expressing (LepRLH) subpopulation at a fast timescale, LepRLH neurons limited feeding or drinking and promoted social interaction despite hunger or thirst. Conversely, neurotensin-expressing LH neurons preferentially encoded water despite hunger pressure and promoted water seeking, while relegating social needs. Thus, hunger and thirst gate both LH populations in a complementary manner to enable the flexible fulfillment of multiple essential needs.
EndophilinA-dependent coupling between activity-induced calcium influx and synaptic autophagy is disrupted by a Parkinson-risk mutation
Authors: Adekunle T. Bademosi, Marianna Decet, Sabine Kuenen, Carles Calatayud, Jef Swerts, Sandra F. Gallego, Nils Schoovaerts, Spyridoula Karamanou, Nikolaos Louros, Ella Martin, Jean-Baptiste Sibarita, Katlijn Vints, Natalia V. Gounko, Frédéric A. Meunier, Anastassios Economou, Wim Versées, Frederic Rousseau, Joost Schymkowitz, Sandra-F. Soukup, Patrik Verstreken
Journal: Neuron (2023)

Neuronal activity causes use-dependent decline in protein function. However, it is unclear how this is coupled to local quality control mechanisms. We show in Drosophila that the endocytic protein Endophilin-A (EndoA) connects activity-induced calcium influx to synaptic autophagy and neuronal survival in a Parkinson disease-relevant fashion. Mutations in the disordered loop, including a Parkinson disease-risk mutation, render EndoA insensitive to neuronal stimulation and affect protein dynamics: when EndoA is more flexible, its mobility in membrane nanodomains increases, making it available for autophagosome formation. Conversely, when EndoA is more rigid, its mobility reduces, blocking stimulation-induced autophagy. Balanced stimulation-induced autophagy is required for dopagminergic neuron survival, and a variant in the human ENDOA1 disordered loop conferring risk to Parkinson disease also blocks nanodomain protein mobility and autophagy both in vivo and in human-induced dopaminergic neurons. Thus, we reveal a mechanism that neurons use to connect neuronal activity to local autophagy and that is critical for neuronal survival.
Monocytes re-enter the bone marrow during fasting and alter the host response to infection
Authors: Henrike Janssen, Florian Kahles, Dan Liu, Jeffrey Downey, Laura L. Koekkoek, Vladimir Roudko, Darwin D’Souza, Cameron S. McAlpine, Lennard Halle, Wolfram C. Poller, Christopher T. Chan, Shun He, John E. Mindur, Máté G. Kiss, Sumnima Singh, Atsushi Anzai, Yoshiko Iwamoto, Rainer H. Kohler, Kashish Chetal, Ruslan I. Sadreyev, Ralph Weissleder, Seunghee Kim-Schulze, Miriam Merad, Matthias Nahrendorf, Filip K. Swirski
Journal: Immunity (2023)
Intratumoral CD8+ T cells with a tissue-resident memory phenotype mediate local immunity and immune checkpoint responses in breast cancer
Authors: Balaji Virassamy, Franco Caramia, Peter Savas, Sneha Sant, Jianan Wang, Susan N Christo, Ann Byrne, Kylie Clarke, Emmaline Brown, Zhi Ling Teo, Bianca von Scheidt, David Freestone, Luke C Gandolfo, Karsten Weber, Julia Teply-Szymanski, Ran Li, Stephen J Luen, Carsten Denkert, Sibylle Loibl, Olivia Lucas, Charles Swanton, Terence P Speed, Phillip K Darcy, Paul J Neeson, Laura K Mackay, Sherene Loi
Journal: Cancer Cell (2023)

CD8+ tumor-infiltrating lymphocytes with a tissue-resident memory T (TRM) cell phenotype are associated with favorable prognosis in patients with triple-negative breast cancer (TNBC). However, the relative contribution of CD8+ TRM cells to anti-tumor immunity and immune checkpoint blockade efficacy in breast cancer remains unknown. Here, we show that intratumoral CD8+ T cells in murine mammary tumors transcriptionally resemble those from TNBC patients. Phenotypic and transcriptional studies established two intratumoral sub-populations: one more enriched in markers of terminal exhaustion (TEX-like) and the other with a bona fide resident phenotype (TRM-like). Treatment with anti-PD-1 and anti-CTLA-4 therapy resulted in expansion of these intratumoral populations, with the TRM-like subset displaying significantly enhanced cytotoxic capacity. TRM-like CD8+ T cells could also provide local immune protection against tumor rechallenge and a TRM gene signature extracted from tumor-free tissue was significantly associated with improved clinical outcomes in TNBC patients treated with checkpoint inhibitors.
Survival by First-line Treatment Type and Timing of Progression Among Follicular Lymphoma Patients: A National Population-based Study in Sweden
Authors: Caroline E. Weibull, Tove Wästerlid, Björn Engelbrekt Wahlin, Per-Ola Andersson, Sara Ekberg, Sandra Lockmer, Gunilla Enblad, Michael J. Crowther, Eva Kimby, Karin E. Smedby
Journal: HemaSphere (2023)

In follicular lymphoma (FL), progression of disease ≤24 months (POD24) has emerged as an important prognostic marker for overall survival (OS). We aimed to investigate survival more broadly by timing of progression and treatment in a national population-based setting. We identified 948 stage II-IV indolent FL patients in the Swedish Lymphoma Register diagnosed 2007–2014 who received first-line systemic therapy, followed through 2020. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated by first POD at any time during follow-up using Cox regression. OS was predicted by POD using an illness-death model. During a median follow-up of 6.1 years (IQR: 3.5–8.4), 414 patients experienced POD (44%), of which 270 (65%) occurred ≤24 months. POD was represented by a transformation in 15% of cases. Compared to progression-free patients, POD increased all-cause mortality across treatments, but less so among patients treated with rituximab(R)-single (HR = 4.54, 95% CI: 2.76-7.47) than R-chemotherapy (HR = 8.17, 95% CI: 6.09-10.94). The effect of POD was similar following R-CHOP (HR = 8.97, 95% CI: 6.14-13.10) and BR (HR = 10.29, 95% CI: 5.60-18.91). The negative impact of POD on survival remained for progressions up to 5 years after R-chemotherapy, but was restricted to 2 years after R-single. After R-chemotherapy, the 5-year OS conditional on POD occurring at 12, 24, and 60 months was 34%, 46%, and 57% respectively, versus 78%, 82%, and 83% if progression-free. To conclude, POD before but also beyond 24 months is associated with worse survival, illustrating the need for individualized management for optimal care of FL patients.
Author Correction: Discovery of 42 genome-wide significant loci associated with dyslexia
Authors: Catherine Doust, Pierre Fontanillas, Else Eising, Scott D. Gordon, Zhengjun Wang, Gökberk Alagöz, Barbara Molz, Stella Aslibekyan, Adam Auton, Elizabeth Babalola, Robert K. Bell, Jessica Bielenberg, Katarzyna Bryc, Emily Bullis, Daniella Coker, Gabriel Cuellar Partida, Devika Dhamija, Sayantan Das, Sarah L. Elson, Teresa Filshtein, Kipper Fletez-Brant, Will Freyman, Pooja M. Gandhi, Karl Heilbron, Barry Hicks, David A. Hinds, Ethan M. Jewett, Yunxuan Jiang, Katelyn Kukar, Keng-Han Lin, Maya Lowe, Jey McCreight, Matthew H. McIntyre, Steven J. Micheletti, Meghan E. Moreno, Joanna L. Mountain, Priyanka Nandakumar, Elizabeth S. Noblin, Jared O’Connell, Aaron A. Petrakovitz, G. David Poznik, Morgan Schumacher, Anjali J. Shastri, Janie F. Shelton, Jingchunzi Shi, Suyash Shringarpure, Vinh Tran, Joyce Y. Tung, Xin Wang, Wei Wang, Catherine H. Weldon, Peter Wilton, Alejandro Hernandez, Corinna Wong, Christophe Toukam Tchakouté, Filippo Abbondanza, Andrea G. Allegrini, Till F. M. Andlauer, Cathy L. Barr, Manon Bernard, Kirsten Blokland, Milene Bonte, Dorret I. Boomsma, Thomas Bourgeron, Daniel Brandeis, Manuel Carreiras, Fabiola Ceroni, Valéria Csépe, Philip S. Dale, Peter F. de Jong, Jean Francois Démonet, Eveline L. de Zeeuw, Yu Feng, Marie-Christine J. Franken, Margot Gerritse, Alessandro Gialluisi, Sharon L. Guger, Marianna E. Hayiou-Thomas, Juan Hernández-Cabrera, Jouke-Jan Hottenga, Charles Hulme, Philip R. Jansen, Juha Kere, Elizabeth N. Kerr, Tanner Koomar, Karin Landerl, Gabriel T. Leonard, Zhijie Liao, Maureen W. Lovett, Heikki Lyytinen, Angela Martinelli, Urs Maurer, Jacob J. Michaelson, Nazanin Mirza-Schreiber, Kristina Moll, Angela T. Morgan, Bertram Müller-Myhsok, Dianne F. Newbury, Markus M. Nöthen, Tomas Paus, Zdenka Pausova, Craig E. Pennell, Robert J. Plomin, Kaitlyn M. Price, Franck Ramus, Sheena Reilly, Louis Richer, Kaili Rimfeld, Gerd Schulte-Körne, Chin Yang Shapland, Nuala H. Simpson, Margaret J. Snowling, John F. Stein, Lisa J. Strug, Henning Tiemeier, J. Bruce Tomblin, Dongnhu T. Truong, Elsje van Bergen, Marc P. van der Schroeff, Marjolein Van Donkelaar, Ellen Verhoef, Carol A. Wang, Kate E. Watkins, Andrew J. O. Whitehouse, Karen G. Wigg, Margaret Wilkinson, Gu Zhu, Beate St Pourcain, Clyde Francks, Riccardo E. Marioni, Jingjing Zhao, Silvia Paracchini, Joel B. Talcott, Anthony P. Monaco, John F. Stein, Jeffrey R. Gruen, Richard K. Olson, Erik G. Willcutt, John C. DeFries, Bruce F. Pennington, Shelley D. Smith, Margaret J. Wright, Nicholas G. Martin, Adam Auton, Timothy C. Bates, Simon E. Fisher, Michelle Luciano
Journal: Nature Genetics (2023)

Methods section, reading "Genomic control.Top SNPs are reported from the more conservative GWAS results adjusted for genomic control (Fig. 1, Extended Data Figs.1234, and Supplementary Tables 1,2, 9 and 10), whereas downstream analyses (including